DESCRIPTION: (Verbatim from the Applicant's Abstract) The dentate gyrus is critical for gating information entry into the intrahippocampal trisynaptic circuit. This proposal will examine the synaptic connectivity of the dentate gyrus, focusing on our discovery of a novel mechanism of synaptic depolarization of dentate granule cells. We recently demonstrated that granule cells are depolarized by a synaptic mechanism which is independent of ionotropic glutamate, GABA A or GABA B receptor activation. Since the submission of our original proposal, we have found that opioid peptides, co-released along with GABA from hilar interneurons, are the likely candidates generating the granule cell synaptic depolarization. In this revised proposal, we will characterize the opioid-dependent granule cell depolarization, and investigate the its role in the propagation of normal and pathologic synaptic transmission within the hippocampus. Our initial studies will assess the contribution of various opiate peptides and opioid receptors. To the granule cell depolarization. Additional experiments will characterize the ionic nature of the granule cell depolarization. Other studies will extend our preliminary findings that the opioid-dependent granule cell depolarization can be elicited by electrical stimulation or by elevating extracellular K+. Several studies will investigate the role of the granule cell synaptic depolarization in gating the entry of physiologic and pathophysiologic synaptic activity into the hippocampal circuit, using in vitro and in vivo electrical stimulation (kindling) protocols. Additional studies will examine the effects of prolonged seizure activity and synaptic reorganization on the granule cell depolarization. Lastly, we will use paired recordings of monosynaptically coupled cells to directly examine the synaptic connectivity of dentate granule cells and hilar interneuron subtypes. Together, these studies should provide valuable information describing the generation of the opioid-dependent granule cell depolarization, and its involvement in normal and pathophysiologic synaptic transmission in the hippocampus.